“The COVID-19 pandemic provoked a global health crisis and highlighted the need for new therapeutic strategies. In this study, we explore the potential of the molecular consortia of cannabidiol (CBD) and non-steroidal anti-inflammatory drugs (NSAIDs) as novel antiviral dual-target agents against SARS-CoV-2/COVID-19. CBD is a natural compound with a wide range of therapeutic activities, including antiviral and anti-inflammatory properties, while NSAIDs are commonly used to mitigate the symptoms of viral infections. Chemical modifications of CBD with NSAIDs were performed to obtain dual-target agents with enhanced activity against SARS-CoV-2. The synthesised compounds were characterised using spectroscopic techniques. The biological activity of three molecular consortia (CBD-ibuprofen, CBD-ketoprofen, and CBD-naproxen) was evaluated in cell lines transduced with vesicular stomatitis virus-based pseudotypes bearing the SARS-CoV-1 or SARS-CoV-2 spike proteins or infected with influenza virus A/Puerto Rico/8/34. The results showed that some CBD-NSAID molecular consortia have superior antiviral activity against SARS-CoV-1 and SARS-CoV-2, but not against the influenza A virus. This may suggest a potential therapeutic role for these compounds in the treatment of emerging coronavirus infections. Further studies are needed to investigate the efficacy of these compounds in vivo, and their potential use in clinical settings. Our findings provide a promising new approach to combatting current and future viral emergencies.”

https://pubmed.ncbi.nlm.nih.gov/37513798/

https://www.mdpi.com/2076-0817/12/7/951

“In the present study, the antiviral activity of cannabinoids isolated from Cannabis sativa L. was assessed in vitro against a panel of SARS-CoV-2 variants, indicating cannabidiolic acid (CBDA) was the most active. To overcome the instability issue of CBDA, its methyl ester was synthesized and tested for the first time for its antiviral activity. CBDA methyl ester showed a neutralizing effect on all the SARS-CoV-2 variants tested with greater activity than the parent compound. Its stability in vitro was confirmed by ultra-high-performance liquid chromatography (UHPLC) analysis coupled with high-resolution mass spectrometry (HRMS). In addition, the capacity of both CBDA and its derivative to interact with the virus spike protein was assessed in silico. These results showed that CBDA methyl ester can be considered as a lead compound to be further developed as a new effective drug against COVID-19 infection.”

https://pubmed.ncbi.nlm.nih.gov/37402317/

https://pubs.acs.org/doi/10.1021/acs.jnatprod.3c00111?cookieSet=1

“Cannabidiol (CBD) has a number of biological effects by acting on the cannabinoid receptors CB₁ and CB₂. CBD may be involved in anti-inflammatory processes via CB₁ and CB₂ receptors, resulting in a decrease of pro-inflammatory cytokines. However, CBD’s poor aqueous solubility is a major issue in pharmaceutical applications. The aim of the present study was to develop and evaluate a CBD nasal spray solution. A water-soluble CBD was prepared by complexation with β-cyclodextrin (β-CD) at a stoichiometric ratio of 1:1 and forming polymeric micelles using poloxamer 407. The mixture was then lyophilized and characterized using FT-IR, DSC, and TGA. CBD-β-CD complex-polymeric micelles were formulated for nasal spray drug delivery. The physicochemical properties of the CBD-β-CD complex-polymeric micelle nasal spray solution (CBD-β-CDPM-NS) were assessed.

The results showed that the CBD content in the CBD-β-CD complex polymeric micelle powder was 102.1 ± 0.5%. The CBD-β-CDPM-NS was a clear colorless isotonic solution. The particle size, zeta potential, pH value, and viscosity were 111.9 ± 0.7 nm, 0.8 ± 0.1 mV, 6.02 ± 0.02, and 12.04 ± 2.64 cP, respectively. This formulation was stable over six months at ambient temperature. The CBD from CBD-β-CDPM-NS rapidly released to 100% within 1 min. Ex-vivo permeation studies of CBD-β-CDPM-NS through porcine nasal mucosa revealed a permeation rate of 4.8 μg/cm²/min, which indicated that CBD was effective in penetrating nasal epithelial cells. CBD-β-CDPM-NS was tested for its efficacy and safety in terms of cytokine production from nasal immune cells and toxicity to nasal epithelial cells. The CBD-β-CDPM-NS was not toxic to nasal epithelial at the concentration of CBD equivalent to 3.125-50 μg/mL.

When the formulation was subjected to bioactivity testing against monocyte-like macrophage cells, it proved that the CBD-β-CDPM-NS has the potential to inhibit inflammatory cytokines. CBD-β-CDPM-NS demonstrated the formulation’s ability to reduce the cytokine produced by S-RBD stimulation in ex vivo porcine nasal mucosa in both preventative and therapeutic modes.”

https://pubmed.ncbi.nlm.nih.gov/37182795/

“In vitro and ex vivo experiments were performed to evaluate the efficacy and safety of CBD.

•CBD-β-CD complexed in poloxamer micelles were 4,275 times water-soluble than CBD.

•CBD-β-CD complexed in poloxamer micelles was developed and evaluated as nasal spray solution.

•The developed nasal spray reduced SARS-CoV-2-induced pro-inflammatory cytokines.”

https://www.sciencedirect.com/science/article/pii/S0378517323004556?via%3Dihub

“To control the COVID-19 pandemic, antivirals that specifically target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently required. The 3-chymotrypsin-like protease (3CLpro) is a promising drug target since it functions as a catalytic dyad in hydrolyzing polyprotein during the viral life cycle. Bioactive peptides, especially food-derived peptides, have a variety of functional activities, including antiviral activity, and also have a potential therapeutic effect against COVID-19.

In this study, the hemp seed trypsinized peptidome was subjected to computer-aided screening against the 3CLpro of SARS-CoV-2. Using predictive trypsinized products of the five major proteins in hemp seed (i.e., edestin 1, edestin 2, edestin 3, albumin, and vicilin), the putative hydrolyzed peptidome was established and used as the input dataset.

To select the Cannabis sativa antiviral peptides (csAVPs), a predictive bioinformatic analysis was performed by three webserver screening programs: iAMPpred, AVPpred, and Meta-iAVP. The amino acid composition profile comparison was performed by COPid to screen for the non-toxic and non-allergenic candidates, ToxinPred and AllerTOP and AllergenFP, respectively. GalaxyPepDock and HPEPDOCK were employed to perform the molecular docking of all selected csAVPs to the 3CLpro of SARS-CoV-2. Only the top docking-scored candidate (csAVP4) was further analyzed by molecular dynamics simulation for 150 nanoseconds.

Molecular docking and molecular dynamics revealed the potential ability and stability of csAVP4 to inhibit the 3CLpro catalytic domain with hydrogen bond formation in domain 2 with short bonding distances. In addition, these top ten candidate bioactive peptides contained hydrophilic amino acid residues and exhibited a positive net charge.

We hope that our results may guide the future development of alternative therapeutics against COVID-19.”

https://pubmed.ncbi.nlm.nih.gov/36615263/

https://www.mdpi.com/1420-3049/28/1/50

“The emergence of a novel coronavirus that later on rendered a global pandemic, caused desperation within the communities and drove increased interest in exploring medicinal plant-based therapeutics to treat and prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infections.

Many medicinal plants have been reported to have antiviral, anti-inflammatory, and immunomodulatory effects that hinder, cure, or ease the symptoms of COVID-19 infection.

This exploratory study seeks to dock the active components of Cannabis sativa, a natural plant with several pharmacological and biological properties, with the angiotensin-converting enzyme II (ACE2) receptor. A total of 3 C. sativa active components have been found to bind to the ACE2 protein active site and could inhibit spike binding, although they do not compete directly with the receptor-binding domain (RBD) of SARS-CoV-2. 6-Prenylapigenin, cannabivarin (CBN-C3), and Δ8-tetrahydrocannabinolic acid-A (Δ8-THCA) have a greater affinity (-8.3, -8.3, and -8.0 kcal/mol, respectively) and satisfactory interaction with ACE2 than its inhibitor MLN-4760 (-7.1 kcal/mol).

These potential drugs with higher affinity for the ACE2 receptor and adequate absorption, distribution, metabolism, excretion, and toxicity (ADMET) values are candidates for treating or preventing SARS-CoV-2 infections. In vitro and in vivo investigations are needed to evaluate further the efficacy and toxicity of these hit compounds.”

https://pubmed.ncbi.nlm.nih.gov/36582392/

“Our research reveals that 6-prenylapigenin, CBN-C3, and 8-THCA are 3 compounds that have shown promising binding and drug-likeness outcomes, which should be evaluated further for pharmaceutical development research.”

https://journals.sagepub.com/doi/10.1177/11779322221145380

“Since the start of the COVID-19 global pandemic, our understanding of the underlying disease mechanism and factors associated with the disease severity has dramatically increased. A recent study investigated the relationship between substance use disorders (SUD) and the risk of severe COVID-19 in the United States and concluded that the risk of hospitalization and death due to COVID-19 is directly correlated with substance abuse, including opioid use disorder (OUD) and cannabis use disorder (CUD). While we found this analysis fascinating, we believe this observation may be biased due to comorbidities (such as hypertension, diabetes, and cardiovascular disease) confounding the direct effect of SUD on severe COVID-19 illness. To answer this question, we sought to investigate the causal relationship between substance abuse and medication-taking history (as a proxy trait for comorbidities) with the risk of COVID-19 adverse outcomes.

Our Mendelian randomization analysis confirms the causal relationship between OUD and severe COVID-19 illness but suggests an inverse causal effect for cannabinoids.

Considering that COVID-19 mortality is largely attributed to disturbed immune regulation, the possible modulatory impact of cannabinoids in alleviating cytokine storms merits further investigation.”

https://pubmed.ncbi.nlm.nih.gov/36583016/

“In conclusion, our MR analysis confirms the causal relationship between opioids and severe COVID-19 illness. However, our MR analysis questions the validity of the causal relationship between CUD and COVID-19 severe illness. A recent study showed that treatment with cannabis compounds significantly reduces cytokine secretion in lung epithelial cells and, therefore, may be useful in alleviating severe symptoms in COVID-19 patients. The fact that a great deal of COVID-19 mortality is attributed to immune dysregulation and cytokine storm, the possible modulatory impact of cannabinoids merits further investigation. Besides, it is shown that cannabidiol (CBD) blocks viral replication in lung epithelial cells through the up-regulation of endoplasmic reticulum (ER) stress response and interferon signaling pathways. Intriguingly, medical history of oral CBD use was associated with a reduced COVID-19 test-positivity rate.”

https://www.frontiersin.org/articles/10.3389/fgene.2022.1070428/full

“Cannabis sativa is one of the first medicinal plants used by humans. Its medical use remains controversial because it is a psychotropic drug whose use has been banned. Recently, however, some countries have approved its use, including for recreational and medical purposes, and have allowed the scientific study of its compounds. Cannabis is characterized by the production of special types of natural products called phytocannabinoids that are synthesized exclusively by this genus. Phytocannabinoids and endocannabinoids are chemically different, but both pharmacologically modulate CB1, CB2, GRP55, GRP119 and TRPV1 receptor activities, involving activities such as memory, sleep, mood, appetite and motor regulation, pain sensation, neuroinflammation, neurogenesis and apoptosis. Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are phytocannabinoids with greater pharmacological potential, including anti-inflammatory, neuroprotective and anticonvulsant activities. Cannabidiol is showing promising results for the treatment of COVID-19, due to its capability of acting on the unleashed cytokine storm, on the proteins necessary for both virus entry and replication and on the neurological consequences of patients who have been infected by the virus. Here, we summarize the latest knowledge regarding the advantages of using cannabinoids in the treatment of COVID-19.”

https://pubmed.ncbi.nlm.nih.gov/36556483/

“Cannabinoids, especially CBD, appear to be promising in the treatment of COVID-19, as an adjuvant of current antiviral drugs, reducing lung inflammation by decreasing chemokines and cytokines secreted by the cells of the immune system or mediating in the CNS reducing morbidity as fear, anxiety, stress, sleep disorders. However, more research and clinical studies are necessary, especially to establish the effects of their long-term use. In any case, many countries are allowing the use of medical cannabis and this plant, which has been used since ancient times, could be a natural therapeutic alternative for COVID-19 infected patients, but there is still a long way to go for its acceptance and use in routine clinical practice.”

https://www.mdpi.com/2075-1729/12/12/2117